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. 2011;6(10):e26262.
doi: 10.1371/journal.pone.0026262. Epub 2011 Oct 20.

Dietary vitamin D3 supplements reduce demyelination in the cuprizone model

Stig Wergeland  1 , Øivind Torkildsen, Kjell-Morten Myhr, Lage Aksnes, Sverre Jarl Mørk, Lars Bø
Affiliations

Dietary vitamin D3 supplements reduce demyelination in the cuprizone model

Stig Wergeland et al. PLoS One. 2011.

Abstract

Vitamin D is emerging as a probably important environmental risk factor in multiple sclerosis, affecting both susceptibility and disease progression. It is not known to what extent this effect is due to a modulation of peripheral lymphocyte function, or to intrathecal effects of vitamin D. We investigated the effect of dietary vitamin D3 content on de/remyelination in the cuprizone model, which is a well established toxic model of demyelination, with no associated lymphocyte infiltration. The mice received diets either deficient of (<50 IU/kg), or supplemented with low (500 IU/kg), high (6200 IU/kg) or very high (12500 IU/kg) amounts of vit D3. Cuprizone (0.2%) was added to the diet for six weeks, starting two weeks after onset of the experimental diets. Mouse brain tissue was histopathologically evaluated for myelin and oligodendrocyte loss, microglia/macrophage activation, and lymphocyte infiltration after six weeks of cuprizone exposure, and two weeks after discontinuation of cuprizone exposure. High and very high doses of vitamin D3 significantly reduced the extent of white matter demyelination (p = 0.004) and attenuated microglia activation (p = 0.001). No differences in the density of oligodendrocytes were observed between the diet groups. Two weeks after discontinuation of cuprizone exposure, remyelination was only detectable in the white matter of mice receiving diets deficient of or with low vitamin D3 content. In conclusion, high dietary doses of vitamin D3 reduce the extent of demyelination, and attenuate microglia activation and macrophage infiltration in a toxic model of demyelination, independent of lymphocyte infiltration.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Serum levels of the vitamin D3 metabolite 25-OH-vit. D3.
After introduction of the experimental diets the serum levels of mice fed a diet with high vit. D3 content (6200 or 12500 IU/kg) are significantly higher than in mice fed a diet containing a very low (<50 IU/kg) or low (500 IU/kg) amounts of vit. D3 (* p<0.0005). This difference persisted throughout the study period. However, there were no significant differences between the two high-content groups (p = 0.70) or between the two low-content groups (p = 0.46).
Figure 2
Figure 2. Demyelination and microglia/macrophage activation in the midline of corpus callosum after six weeks of cuprizone exposure in the different diet groups.
The mice receiving a diet deficient (<50 IU/kg) or low (500 IU/kg) in vitamin D3 content are extensively demyelinated, and the density of activated microglia and macrophages is high. The mice receiving a diet with higher vitamin D3 content (6200 or 12500 IU/kg), are significantly less demyelinated (p = 0.004), and the density of activated microglia and macrophages is significantly lower (p = 0.001). All images at 40×.
Figure 3
Figure 3. LFB and PLP scores.
A: Semiquantitative scores of sections histochemically stained for LFB. A score of 3 indicates normal or full myelination, while a score of 0 indicates complete demyelination. Top panel represents the scores after six weeks of cuprizone exposure, bottom panel two weeks after discontinuation of the cuprizone exposure. Bars represent mean score, error bars represents ±1 SD. * p = 0.004. B: Relative area immunopositive for PLP in the midline of corpus callosum. Top panel represents the scores after six weeks of cuprizone exposure, bottom panel two weeks after discontinuation of the cuprizone exposure. Bars represent mean score, error bars represents ±1 SD. ‡ p = 0.02.
Figure 4
Figure 4. Remyelination and microglia/macrophage activation in the midline of corpus callosum two weeks after discontinuation of cuprizone exposure in the different diet groups.
Only the mice given a diet containing <50 or 500 IU/kg of vitamin D3 had an increase in LFB semiquantitative scores compared to at the discontinuation of the cuprizone exposure (p = 0.003). There is no significant difference in the mean LFB score between the diet groups (p = 0.74), or in the PLP-immunopositive area (p = 0.99). Microglia/macrophage infiltration is reduced two weeks after ending cuprizone exposure compared to after 6 weeks cuprizone exposure. The reduction in Mac-3 immunopositive cells is most evident in the groups fed the diets with the lower (<50 or 500 IU/kg) vitamin D3 content (<50 IU/kg: p = 0.018, 500 IU/kg: p = 0.014). All images at 40×.
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References

    1. Grytten N, Glad SB, Aarseth JH, Nyland H, Midgard R, et al. A 50-year follow-up of the incidence of multiple sclerosis in Hordaland County, Norway. Neurology. 2006;66:182–186. - PubMed
    1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–1517. S0140-6736(08)61620-7 [pii];10.1016/S0140-6736(08)61620-7 [doi] - PubMed
    1. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008;194:7–17. - PubMed
    1. Myhr KM. Vitamin D treatment in multiple sclerosis. J Neurol Sci. 2009;286:104–108. S0022-510X(09)00586-3 [pii];10.1016/j.jns.2009.05.002 [doi] - PubMed
    1. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296:2832–2838. - PubMed

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